Secondary Acute Myeloid Leukemia
Conditions
Brief summary
This phase Ib/II trial finds out the best dose and effect of cladribine and low dose cytarabine when given in combination with uproleselan in treating patients with treated secondary acute myeloid leukemia. Chemotherapy drugs, such as uproleselan, cladribine, and low dose cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Detailed description
PRIMARY OBJECTIVE: I. To determine the safety, tolerability, and recommended phase II dose (RP2D) of uproleselan combined with cladribine + low dose cytarabine (LDAC) in patients with treated-secondary acute myeloid leukemia (AML) (ts-AML). SECONDARY OBJECTIVES: I. To assess the efficacy (overall response rate \[ORR\], complete response \[CR\], complete response without blood count recovery \[CRi\], CR with partial hematologic recovery \[CRh\], partial response \[PR\], or morphologic leukemia-free state of uproleselan combined with cladribine + LDAC in patients with ts-AML. II. To assess the rate of minimal residual disease (MRD) negativity by flow cytometry at response. III. To assess overall survival (OS), remission duration (CRd), and progression-free survival (PFS) in patients with ts-AML treated with uproleselan combined with cladribine + LDAC. IV. To assess the rate of complete cytogenetic response (CCyR) in patients with ts-AML with abnormal baseline karyotype, treated with uproleselan combined with cladribine + LDAC. V. To assess toxicity and induction mortality of patients with AML treated with uproleselan added to cladribine + LDAC. EXPLORATORY OBJECTIVES: I. To explore biomarkers of response and resistance in patients with ts-AML treated with uproleselan combined with cladribine + LDAC. II. To examine the correlation of E-selectin ligand-forming glycosylation genes of leukemic blasts with clinical outcome. OUTLINE: This is a phase I, dose-escalation study of cladribine and cytarabine followed by a phase II study. INDUCTION THERAPY: Patients receive uproleselan intravenously (IV) over 20 minutes on day 1 and every (Q) 12 hours on days 2-12, cladribine IV over 1-2 hours on days 1-5 and cytarabine subcutaneously (SC) twice daily (BID) on days 1-10 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a second induction cycle. CONSOLIDATION/MAINTENANCE THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q12 hours on days 2-1. Patients who have achieved at least CR/CRi or morphologic leukemia-free state after induction therapy receive uproleselan IV once daily (QD) on days 1-12. Patients also receive cladribine IV over 1-2 hours on days 1-3 and cytarabine SC BID on days 1-10. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6-12 months.
Interventions
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with a diagnosis of treated secondary-AML (TS-AML) who have not received therapy for their AML will be eligible. 2. TS-AML is defined as AML arising from a previously treated antecedent myeloid neoplasm (myelodysplastic syndrome or myeloproliferative neoplasm that has been previously treated with hypomethylating agents). 3. Patients must be at least 7 days from their last therapy for the antecedent myeloid neoplasm 4. Age \>/= 18 years. 5. Adequate organ function as defined below: * liver function (total bilirubin \< 2mg/dL, AST and/or ALT \<3 x ULN - or \<5 x ULN if related to leukemic involvement) * kidney function (creatinine \< 1.5 x ULN ). * known cardiac ejection fraction of \> or = 45% within the past 6 months 6. ECOG performance status of ≤ 2. 7. A negative urine or serum pregnancy test is required within 1 week for all women of childbearing potential prior to enrolling on this trial. 8. Patient must have the ability to understand the requirements of the study and informed consent. A signed informed consent by the patient is required prior to their enrollment on the protocol.
Exclusion criteria
1. Pregnant women are excluded from this study because the agents used in this study have the potential for teratogenic or abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided. 2. Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 3. Patients with documented hypersensitivity to any of the components of the chemotherapy program. 4. Men and women of childbearing potential who do not practice contraception. Women of childbearing potential and men must agree to use contraception prior to study entry and for the duration of study participation. 5. Prior treatment with uproleselan. 6. Patients with a diagnosis of acute promyelocytic leukemia (AML-M3) will be excluded from this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose | Up to two courses of Induction therapy, each course is approximately 4 weeks +/- 7 days | During safety lead-in, we will use the Bayesian optimal interval (BOIN) design to identify the RP2D of the combination therapy. If the observed DLT rate at the current dose is . 0.236, escalate the dose to the next higher dose level; . if the observed DLT rate at the current dose is . 0.359, de-escalate the dose to the next lower dose level; otherwise, stay at the current dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Response | Up to 3 years, 4 months and 14 days | Response is Complete Remission (CR) + Complete Remission Without Count Recovery (CRi) + Morphologic Leukemia-Free State (MLFS) - CR is Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. CRi is Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L). MLFS is Bone marrow differential showing \< 5% blasts, no evidence of peripheral blasts or extramedullary disease, but without peripheral blood count recovery to neutrophil count . 1.0 x 10\^9/L \& platelet count . 100 x 10\^9/L. |
| Number of Participants With Complete Response (CR) | Up to 3 years, 4 months and 14 days | Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. |
| Number of Participants With Complete Remission Without Blood Count Recovery (CRi) | Up to 3 years, 4 months and 14 days | Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L). |
| Number of Participants to Reach Morphologic Leukemia-free State (MLFS) | Up to 3 years, 4 months and 14 days | Bone marrow differential showing \< 5% blasts, no evidence of peripheral blasts or extramedullary disease, but without peripheral blood count recovery to neutrophil count . 1.0 x 10\^9/L \& platelet count . 100 x 10\^9/L. |
| Number of Minimal Residual Disease (MRD) Negativity in Responders | Up to 3 years, 4 months and 14 days | Measures the Minimal Residual Disease (MRD) negativity in participants who achieve Complete Remission (CR) or Complete remission without count recovery (CRi) - CR is Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. CRi is Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L). |
| Overall Survival | From treatment start to the date of death or last follow-up, whichever occurred first, Up to 3 years, 4 months and 14 days | Time from date of treatment start until date of death due to any cause. |
| Event-free Survival | From treatment start to date of death, relapse or last follow-up, whichever occurred first, Up to 3 years, 4 months and 14 days | Time from date of treatment start until the date of failure or death from any cause. |
| The Number of Participants With Complete Cytogenetic Response (CCyR) | Up to 3 years, 4 months and 14 days | To assess the rate of complete cytogenetic response (CCyR) in patients with abnormal baseline karyotype, treated with uproleselan combined with cladribine + LDAC. Participants were evaluated for abnormal baseline karyotype and evaluated again after treatment. |
| Induction Mortality, Number of Participants | Up to two courses of Induction therapy, each course is approximately 4 weeks +/- 7 days | Number of participants who died during the induction period of therapy. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTapan M Kadia
M.D. Anderson Cancer Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ph 1 Treatment Dose Level -1 Cladaribine 3.75mg/m^2 INDUCTION THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q 12 hours on days 2-12, cladribine IV over 1-2 hours on days 1-5 and cytarabine SC BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a second induction cycle.
CONSOLIDATION/MAINTENANCE THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q12 hours on days 2-1. Patients who have achieved at least CR/CRi or morphologic leukemia-free state after induction therapy receive uproleselan IV QD on days 1-12. Patients also receive cladribine IV over 1-2 hours on days 1-3 and cytarabine SC BID on days 1-10. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Cladribine: Given IV
Cytarabine: Given SC
Uproleselan: Given IV | 3 |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 INDUCTION THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q 12 hours on days 2-12, cladribine IV over 1-2 hours on days 1-5 and cytarabine SC BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a second induction cycle.
CONSOLIDATION/MAINTENANCE THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q12 hours on days 2-1. Patients who have achieved at least CR/CRi or morphologic leukemia-free state after induction therapy receive uproleselan IV QD on days 1-12. Patients also receive cladribine IV over 1-2 hours on days 1-3 and cytarabine SC BID on days 1-10. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Cladribine: Given IV
Cytarabine: Given SC
Uproleselan: Given IV | 9 |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 INDUCTION THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q 12 hours on days 2-12, cladribine IV over 1-2 hours on days 1-5 and cytarabine SC BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Patients who do not achieve a CR or CRi after cycle 1 may receive a second induction cycle.
CONSOLIDATION/MAINTENANCE THERAPY: Patients receive uproleselan IV over 20 minutes on day 1 and Q12 hours on days 2-1. Patients who have achieved at least CR/CRi or morphologic leukemia-free state after induction therapy receive uproleselan IV QD on days 1-12. Patients also receive cladribine IV over 1-2 hours on days 1-3 and cytarabine SC BID on days 1-10. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Cladribine: Given IV
Cytarabine: Given SC
Uproleselan: Given IV | 25 |
| Total | 37 |
Baseline characteristics
| Characteristic | Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Total | Ph 1 Treatment Dose Level -1 Cladaribine 3.75mg/m^2 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 23 Participants | 32 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 5 Participants | 1 Participants |
| Age, Continuous | 68 years | 73 years | 73 years | 76 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 24 Participants | 33 Participants | 3 Participants |
| Region of Enrollment United States | 9 participants | 25 participants | 37 participants | 3 participants |
| Sex: Female, Male Female | 4 Participants | 19 Participants | 24 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 13 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 7 / 9 | 24 / 25 |
| other Total, other adverse events | 3 / 3 | 6 / 9 | 22 / 25 |
| serious Total, serious adverse events | 3 / 3 | 3 / 9 | 15 / 25 |
Outcome results
Primary
Recommended Phase II Dose
During safety lead-in, we will use the Bayesian optimal interval (BOIN) design to identify the RP2D of the combination therapy. If the observed DLT rate at the current dose is . 0.236, escalate the dose to the next higher dose level; . if the observed DLT rate at the current dose is . 0.359, de-escalate the dose to the next lower dose level; otherwise, stay at the current dose.
Time frame: Up to two courses of Induction therapy, each course is approximately 4 weeks +/- 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Recommended Phase II Dose | 5 mg/m^2 |
Secondary
Complete Remission Duration
The date of Complete Response to the date of loss of response or last follow-up.
Time frame: From date of CR/CRi to date of disease relapse, death or last follow-up, whichever occurred first, assessed up to 4.5 years
Secondary
Event-free Survival
Time from date of treatment start until the date of failure or death from any cause.
Time frame: From treatment start to date of death, relapse or last follow-up, whichever occurred first, Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Event-free Survival | 0.6 Months |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Event-free Survival | 3.1 Months |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Event-free Survival | 1.7 Months |
Secondary
Induction Mortality, Number of Participants
Number of participants who died during the induction period of therapy.
Time frame: Up to two courses of Induction therapy, each course is approximately 4 weeks +/- 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Induction Mortality, Number of Participants | 0 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Induction Mortality, Number of Participants | 0 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Induction Mortality, Number of Participants | 4 Participants |
Secondary
Number of Minimal Residual Disease (MRD) Negativity in Responders
Measures the Minimal Residual Disease (MRD) negativity in participants who achieve Complete Remission (CR) or Complete remission without count recovery (CRi) - CR is Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. CRi is Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L).
Time frame: Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Number of Minimal Residual Disease (MRD) Negativity in Responders | 1 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Minimal Residual Disease (MRD) Negativity in Responders | 2 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Minimal Residual Disease (MRD) Negativity in Responders | 2 Participants |
Secondary
Number of Participants to Reach Morphologic Leukemia-free State (MLFS)
Bone marrow differential showing \< 5% blasts, no evidence of peripheral blasts or extramedullary disease, but without peripheral blood count recovery to neutrophil count . 1.0 x 10\^9/L & platelet count . 100 x 10\^9/L.
Time frame: Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Number of Participants to Reach Morphologic Leukemia-free State (MLFS) | 1 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants to Reach Morphologic Leukemia-free State (MLFS) | 1 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants to Reach Morphologic Leukemia-free State (MLFS) | 2 Participants |
Secondary
Number of Participants With a Response
Response is Complete Remission (CR) + Complete Remission Without Count Recovery (CRi) + Morphologic Leukemia-Free State (MLFS) - CR is Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts. CRi is Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L). MLFS is Bone marrow differential showing \< 5% blasts, no evidence of peripheral blasts or extramedullary disease, but without peripheral blood count recovery to neutrophil count . 1.0 x 10\^9/L & platelet count . 100 x 10\^9/L.
Time frame: Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Number of Participants With a Response | 1 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants With a Response | 4 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants With a Response | 9 Participants |
Secondary
Number of Participants With Complete Remission Without Blood Count Recovery (CRi)
Have met all criteria for CR, except for either residual neutropenia (ANC \< 1.0 x 10\^9/L) or thrombocytopenia (platelet count \< 100 x 10\^9/L).
Time frame: Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Number of Participants With Complete Remission Without Blood Count Recovery (CRi) | 0 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants With Complete Remission Without Blood Count Recovery (CRi) | 1 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants With Complete Remission Without Blood Count Recovery (CRi) | 5 Participants |
Secondary
Number of Participants With Complete Response (CR)
Disappearance of all clinical and/or radiologic evidence of disease, including extramedullary leukemia. Neutrophil count . 1.0 x 10\^9/L and platelet count . 100 x 10\^9/L, and bone marrow differential showing . 5% blasts.
Time frame: Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Number of Participants With Complete Response (CR) | 0 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants With Complete Response (CR) | 2 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Number of Participants With Complete Response (CR) | 2 Participants |
Secondary
Overall Survival
Time from date of treatment start until date of death due to any cause.
Time frame: From treatment start to the date of death or last follow-up, whichever occurred first, Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants Enrolled in Phase 1b | Overall Survival | 0.8 Months |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Overall Survival | 5.5 Months |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | Overall Survival | 3.8 Months |
Secondary
The Number of Participants With Complete Cytogenetic Response (CCyR)
To assess the rate of complete cytogenetic response (CCyR) in patients with abnormal baseline karyotype, treated with uproleselan combined with cladribine + LDAC. Participants were evaluated for abnormal baseline karyotype and evaluated again after treatment.
Time frame: Up to 3 years, 4 months and 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants Enrolled in Phase 1b | The Number of Participants With Complete Cytogenetic Response (CCyR) | 1 Participants |
| Ph 1 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | The Number of Participants With Complete Cytogenetic Response (CCyR) | 1 Participants |
| Ph 2 Treatment Dose Level 1 Cladaribine 5 mg/m^2 | The Number of Participants With Complete Cytogenetic Response (CCyR) | 2 Participants |